A Nanocomposite Dynamic Covalent Cross-Linked Hydrogel Loaded with Fusidic Acid for Treating Antibiotic-Resistant Infected Wounds

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high levels of morbidity and is considered a difficult-to-treat infection, often requiring nonstandard treatment regimens and antibiotics. Since over 40% of the emerging antibiotic compounds have insufficient solubility that limits their bioavailability and thus efficacy through oral or intravenous administration, it is crucial that alternative drug delivery products be developed for wound care applications. Existing effective treatments for soft tissue MRSA infections, such as fusidic acid (FA), which is typically administered orally, could also benefit from alternative routes of administration to improve local efficacy and bioavailability while reducing the required therapeutic dose. Herein, we report an antimicrobial poly(oligoethylene glycol methacrylate) (POEGMA)-based composite hydrogel loaded with fusidic acid-encapsulating self-assembled polylactic acid-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (PLA-POEGMA) nanoparticles for the treatment of MRSA-infected skin wounds. The inclusion of the self-assembled nanoparticles (380 nm diameter when loaded with fusidic acid) does not alter the favorable mechanical properties and stability of the hydrogel in the context of its use as a wound dressing, while fusidic acid (FA) can be released from the hydrogel over ∼10 h via a diffusion-controlled mechanism. The antimicrobial studies demonstrate a clear zone of inhibition in vitro and a 1−2 order of magnitude inhibition of bacterial growth in vivo in an MRSA-infected full-thickness excisional murine wound model even at very low antibiotic doses. Our approach thus can both circumvent challenges in the local delivery of hydrophobic antimicrobial compounds and directly deliver antimicrobials into the wound to effectively combat methicillin-resistant infections using a fraction of the drug dose required using other clinically relevant strategies

Injectable Macroporous Hydrogels by Combining the Rapid Evaporation of Perfluorocarbon Emulsions with Dynamic Covalent Cross-Linking Chemistry

While injectable hydrogels are significantly less invasive than other available delivery vehicles for cell therapies, the lack of macroporosity in typical injectable hydrogels (and thus the limited free volume available for cell proliferation and nutrient/waste transport) limits the effectiveness of such therapies. Herein, noncytotoxic and rapidly evaporating perfluorocarbon emulsions are combined with in situ gelling dynamic covalently cross-linked hydrogels to create an injectable hydrogel in which macropore generation can occur simultaneously to gelation as the perfluorocarbon component evaporates upon heating to physiological temperature. Macropores can be generated at different densities dependent on the perfluorocarbon concentration both in vitro and in vivo without inducing any significant cytotoxicity or local or systemic inflammatory responses. Furthermore, live/dead imaging showed a significant improvement in the viability of encapsulated cells in porous hydrogels in comparison to nonporous controls, attributed to the improved mass transport achievable in the presence of macropores. The combination of controllable porosity, noncytotoxicity, and ability to incorporate cells into the porous structure via a single injection offers a unique platform that could be adapted for use in cell therapy and/or tissue engineering applications

Injectable Macroporous Hydrogels by Combining the Rapid Evaporation of Perfluorocarbon Emulsions with Dynamic Covalent Cross-Linking Chemistry

While injectable hydrogels are significantly less invasive than other available delivery vehicles for cell therapies, the lack of macroporosity in typical injectable hydrogels (and thus the limited free volume available for cell proliferation and nutrient/waste transport) limits the effectiveness of such therapies. Herein, noncytotoxic and rapidly evaporating perfluorocarbon emulsions are combined with in situ gelling dynamic covalently cross-linked hydrogels to create an injectable hydrogel in which macropore generation can occur simultaneously to gelation as the perfluorocarbon component evaporates upon heating to physiological temperature. Macropores can be generated at different densities dependent on the perfluorocarbon concentration both in vitro and in vivo without inducing any significant cytotoxicity or local or systemic inflammatory responses. Furthermore, live/dead imaging showed a significant improvement in the viability of encapsulated cells in porous hydrogels in comparison to nonporous controls, attributed to the improved mass transport achievable in the presence of macropores. The combination of controllable porosity, noncytotoxicity, and ability to incorporate cells into the porous structure via a single injection offers a unique platform that could be adapted for use in cell therapy and/or tissue engineering applications

Injectable Macroporous Hydrogels by Combining the Rapid Evaporation of Perfluorocarbon Emulsions with Dynamic Covalent Cross-Linking Chemistry

While injectable hydrogels are significantly less invasive than other available delivery vehicles for cell therapies, the lack of macroporosity in typical injectable hydrogels (and thus the limited free volume available for cell proliferation and nutrient/waste transport) limits the effectiveness of such therapies. Herein, noncytotoxic and rapidly evaporating perfluorocarbon emulsions are combined with in situ gelling dynamic covalently cross-linked hydrogels to create an injectable hydrogel in which macropore generation can occur simultaneously to gelation as the perfluorocarbon component evaporates upon heating to physiological temperature. Macropores can be generated at different densities dependent on the perfluorocarbon concentration both in vitro and in vivo without inducing any significant cytotoxicity or local or systemic inflammatory responses. Furthermore, live/dead imaging showed a significant improvement in the viability of encapsulated cells in porous hydrogels in comparison to nonporous controls, attributed to the improved mass transport achievable in the presence of macropores. The combination of controllable porosity, noncytotoxicity, and ability to incorporate cells into the porous structure via a single injection offers a unique platform that could be adapted for use in cell therapy and/or tissue engineering applications